tbuckley/cabot-search huggingface dataset:
An Ode to Kodachrome
Authors: Powell Perng, Kenneth E. Greer
Journal: JAMA Dermatology (2022)

From its debut in 1935 until its discontinuation in 2009, Eastman Kodak Company's Kodachrome color reversal film was a cornerstone for dermatologic teaching innovations that transformed 20th century medical education. This Special Communication examines Kodachrome's contributions to the field of dermatology, as well as its lessons for improving inclusive representation of patients of all skin tones in 21st century dermatologic curricula.Kodachrome's color quality, its slide transparency format, and its broad commercial availability democratized the creation, sharing, and teaching of visual information about skin disease in the 20th century. Kodachrome's usefulness as a complement to bedside teaching modernized medical school curricula, dermatologic conferences, and the American Board of Dermatology certifying examination, which inspired the Kodachrome-style of didactic that remains central to dermatologic training programs today. However, Kodachrome film was also the product of a prejudiced era when color film technology and photographic best practices were optimized for white skin. These biases are still evident in industry standards, photographic techniques, and the historically unjust representation of skin of color in educational resources.Kodachrome film contributed substantially to shaping 20th-century medical education; however, its legacy is a reminder that diverse and inclusive image representation in dermatologic curricula is vital to counteracting implicit biases, correcting assumptions about disease epidemiology, and providing high-quality care for patients of all skin tones. Historical biases that have harmed representations of racial and ethnic minorities in dermatologic curricula are being addressed through improvements in digital photographic technologies, photographic best practices that serve a broader range of skin tones, inclusive skin color representation in contemporary educational resources, and skin-of-color specific curriculum for learners.
Abstract 38: Racial disparities in prostate cancer mortality rates explained by differences in dietary and lifestyle factors
Authors: Emily Rencsok, Michelle Sodipo, Travis Gerke, Konrad Stopsack, Lorelei Mucci
Journal: Cancer Research (2022)

Abstract Introduction: Black men have 2.1 times higher prostate cancer mortality rates than White men in the United States, yet the reasons for this disparity remain unclear. Several dietary and lifestyle factors may influence the risk of developing lethal prostate cancer. This study evaluated to what extent differences in the prevalence of modifiable risk factors by race could explain racial disparities in prostate cancer mortality. Methods: Our study utilized data from the Health Professionals Follow-up Study (HPFS, N=51,529 men, 1986-2016) and the National Health and Nutrition Examination Study (NHANES, 2000-2010). First, we used data from NHANES to estimate the prevalence of three factors among Black and White men: smoking, vitamin D, and coffee. Then, using HPFS, we generated relative risk estimates for lethal prostate cancer for each factor. To estimate the relative prostate cancer burden associated with these risk factors, we calculated the population attributable fraction (PAF) for each factor by self-identified race, defined as the reduction in mortality that would be achieved if the population had been entirely unexposed, compared with the current exposure pattern. We then calculated the difference in the PAF between Black and white men to estimate the difference in mortality reduction between the two groups if all men had been entirely unexposed, assuming causality of risk factors and no effect modification by race. Results: There were notable differences in the prevalence of several risk factors by race. For example, Black men had significantly lower levels of vitamin D[MLA1], were less likely to drink coffee, and had a higher prevalence of smoking compared to white men. We estimated that eliminating these risk factors among Black men could lead to a reduction in prostate cancer mortality that is 4-14% larger compared to eliminating these risk factors among white men. Conclusions: Modifiable lifestyle and dietary factors are potentially responsible for a proportion of the racial disparity in prostate cancer mortality. Our future work will expand the modifiable factors as well as incorporating more contemporary comparisons of the prevalence of these factors to predict future disparities in prostate cancer. Citation Format: Emily Rencsok, Michelle Sodipo, Travis Gerke, Konrad Stopsack, Lorelei Mucci. Racial disparities in prostate cancer mortality rates explained by differences in dietary and lifestyle factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 38.
Abstract 1: Transcriptional profiling of prostatic Skp2 knock-in mouse model and development of the associated prostate organoids for testing Skp2 targeting agents
Authors: Liankun Song, Vyvyan Nguyen, Shan Xu, Jana Yamak, Kia Arabzadehkaffash, Ali Fazelpour, Merci Mino, Matthew Tippin, Shuang Meng, Xiaolin Zi
Journal: Cancer Research (2022)

Abstract S-phase kinase associated protein 2 (Skp2) is a promising drug target as studies have demonstrated that Skp2 is required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb), Pten, or p53 deficient mice. We, therefore, aim to establish CRISPR human Skp2 (hSkp2) knock-in in the prostates of mice to study the molecular profiling features in prostate carcinogenesis. Prostate weights increased in transgenic mice and overexpression of hSkp2 induced prostatic lesions including hyperplasia, mouse prostate intraepithelial neoplasia (mPIN), and carcinoma, which suggested the initial role of hSkp2 in early prostate carcinogenesis. RNAseq results revealed Myl3 and Ctgf as the top down-expressed and up-expressed genes respectively in hSkp2 mice prostates. Gene set enrichment analysis (GSEA) demonstrated the significant upregulations of ribosome and proteasome pathways which had similar alterations in the human prostate cancer dataset with Skp2 overexpression, suggesting the potential role of ribosome biogenesis in prostate tumorigenesis and for drug development. In addition, Skp2 organoids derived from transgenic mice prostates were being developed for convenient and efficient screening of specific Skp2 inhibitors. Flavokawain A (FKA) and Skp2 inhibitor C1 both selectively decreased the viability and altered the morphologies of hSkp2 organoids, meanwhile FKA exhibited less toxicity on wild-type organoids. Citation Format: Liankun Song, Vyvyan Nguyen, Shan Xu, Jana Yamak, Kia Arabzadehkaffash, Ali Fazelpour, Merci Mino, Matthew Tippin, Shuang Meng, Xiaolin Zi. Transcriptional profiling of prostatic Skp2 knock-in mouse model and development of the associated prostate organoids for testing Skp2 targeting agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1.
Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study
Authors: Yinan Zheng, Brian T. Joyce, Shih-Jen Hwang, Jiantao Ma, Lei Liu, Norrina B. Allen, Amy E. Krefman, Jun Wang, Tao Gao, Drew R. Nannini, Haixiang Zhang, David R. Jacobs, Myron D. Gross, Myriam Fornage, Cora E. Lewis, Pamela J. Schreiner, Stephen Sidney, Dongquan Chen, Philip Greenland, Daniel Levy, Lifang Hou, Donald M. Lloyd-Jones
Journal: Circulation (2022)

Cardiovascular health (CVH) from young adulthood is strongly associated with an individual's future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD.
Abstract 1592: Pulsatile Myc expression as a source of Myc heterogeneity in cancer cells
Authors: Chad Liu, Karen Gascoigne
Journal: Cancer Research (2022)

Abstract Myc is the most commonly amplified oncogene, and is known to play critical roles in cancer establishment and maintenance. Myc expression heterogeneity has also been linked to cancer drug resistance; however, the source of this heterogeneity remains poorly characterized. Even in isogenic cancer cell lines, we found that Myc is one of the most heterogeneously expressed transcription factors at the single-cell level. This heterogeneity is independent of cell cycle progression, local cell density, and p53/p21 signaling. To elucidate the source and duration of Myc heterogeneity, we endogenously tagged Myc with a fluorescent protein and used long-term live-cell imaging techniques to monitor Myc expression over time at single-cell resolution. Surprisingly, we found that Myc expression is pulsatile, explaining why Myc expression appears heterogeneous at a given point in time. Furthermore, we found that Myc dynamics are heterogeneous, and the dynamics are not always heritable. Additionally, Myc pulse amplitude is correlated with the duration of G1 and the overall cell cycle, suggesting that the pulses may be a mechanism for escaping many chemotherapy agents. Finally, we show that Myc pulses are primarily transcription-driven and controlled by at least one negative feedback loop. Our findings demonstrate for the first time that Myc expression is pulsatile, and provide insights into Myc regulation in cancer. Citation Format: Chad Liu, Karen Gascoigne. Pulsatile Myc expression as a source of Myc heterogeneity in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1592.
Abstract 5426: Down-regulation of cancer metabolism enhances radiosensitivity by impairing the heat shock response
Authors: Melissa Schwab, Katharina Thunborg, Omid Azimzadeh, Christine von Toerne, Maxim Shevtsov, Masa Zdralevic, Jacques Pouyssegur, Kathrin Renner, Marina Kreutz, Peter Vaupel, Gabriele Multhoff
Journal: Cancer Research (2022)

Abstract Therapy (radiation) resistance can, inter alia, be caused by an increased lactate dehydrogenase (LDH) activity, elevated concentrations of the oncometabolite lactate and an overexpression of anti-apoptotic heat shock proteins (HSPs). In this study we aimed to break radioresistance by targeting the cancer metabolism. We could show, for the first time, that the lactate metabolism and heat shock response are co-regulated in two cancer cell systems (murine B16F10 melanoma cells, human LS174T colorectal adenocarcinoma cells). A CRISPR/Cas9 induced double knockout of LDHA/B (LDH−/−) as well as a pharmacological inhibition of LDH by Oxamate or GNE-140 reduces tumor growth, ROS production and synthesis of different HSPs, including Hsp90, Hsp70 and Hsp27. Moreover, the membrane Hsp70 density was significantly reduced on tumor cells after inhibition of the LDH activity as a consequence of a down-regulated lipid metabolism affecting the Hsp70-anchoring, tumor-specific glycosphingolipid Gb3. Our results demonstrate that influencing cancer metabolism increases radiation sensitivity by an impairment of the stress response. Since presently available LDH inhibitors have a low stability and high toxicity in vivo, we are currently investigating more potent LDH inhibitors with a beneficial safety profile. In summary, targeting the lactate metabolism provides a promising strategy to improve radiosensitivity by impairing the stress response. Citation Format: Melissa Schwab, Katharina Thunborg, Omid Azimzadeh, Christine von Toerne, Maxim Shevtsov, Masa Zdralevic, Jacques Pouyssegur, Kathrin Renner, Marina Kreutz, Peter Vaupel, Gabriele Multhoff. Down-regulation of cancer metabolism enhances radiosensitivity by impairing the heat shock response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5426.
Abstract 3747: RPS3 positively regulates nucleotide excision repair with respect to XP-D and skin cancers
Authors: Joon Kim, Yong-Joon Park, Tae Sung Kim, Woo Sung Ahn, Hag Dong Kim
Journal: Cancer Research (2022)

Abstract Ribosomal protein S3 (rpS3) is a multifunctional protein working in translation, DNA repair, cancer, apoptosis etc. UV induced DNA damage is repaired by the nucleotide excision repair (NER) pathways; defects in these pathways lead to a genetic instability known as xeroderma pigmentosum (XP) eventually developing skin cancers. We discovered that rpS3 associates with transcription factor IIH (TFIIH) via an interaction with the xeroderma pigmentosum complementation group D (XPD) protein and complements its function in the NER pathway. Here, we showed that XP-D cells overexpressing rpS3 showed markedly increased resistance to UV through XPD and rpS3 interaction thus augmenting the helicase activity of XPD protein. Additionally, the knockdown of rpS3 caused reduced NER efficiency and the subsequent addition of rpS3 restored the helicase activity of the TFIIH complex in cells. We present data suggesting that rpS3 is involved in post-excision processing in NER, assisting TFIIH in expediting the repair process by increasing its turnover rate when DNA is damaged. We also propose that rpS3 is a novel accessory protein of the NER pathway and its recruitment to the repair machinery upon UV damage augments repair efficiency by enhancing XPD helicase function and increasing its turnover rate, thus facilitating DNA repair. In addition to this, manipulations of rpS3 gene could complement XP-D phenotype and prevent UV damage and skin cancer occurrence. Animal studies strongly indicate that these result could be applied not only for the development of cancer drugs but also for cosmeceuticals. [1] FASEB J. (2020) 34: 8102 [2] Cell &amp; Mol Life Sci (2021) 78: 3591 Citation Format: Joon Kim, Yong-Joon Park, Tae Sung Kim, Woo Sung Ahn, Hag Dong Kim. RPS3 positively regulates nucleotide excision repair with respect to XP-D and skin cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3747.
Abstract 5175: Novel approach for glioblastoma characterization via tumor specific extracellular vesicles
Authors: Tiffaney Hsia, Anudeep Yekula, Syeda M. Batool, Bob S. Carter, Leonora Balaj
Journal: Cancer Research (2022)

Abstract INTRODUCTION: The utility of photosensitizers (PS), such as 5-Aminolevulinic acid (5-ALA), has been limited to fluorescence-guided surgery (FGS) and photodynamic therapy. The downstream metabolism of 5-ALA results in tumor-specific, highly selective accumulation of PpIX, an endogenous porphyrin, in tumor cells. We have previously reported evidence of PpIX in EVs derived from the plasma of glioblastoma (GBM) patients. Here, we characterize the tumor-specific nature of PpIX fluorescent EVs through quantification of their cargo, demonstrating their utility in the advancement of liquid biopsy for GBM diagnosis and management. METHODS: Fluorescence activated cell sorting was adapted for nanoparticle isolation and PpIX fluorescent EVs were sorted from plasma collected from patients (N = 8) diagnosed with GBM, undergoing FGS. RNA cargo was extracted and quantified via low input RNA-Seq. Matching patient tumor and total plasma EVs along with healthy control plasma EVs (N = 8) were sequenced in parallel. SUMMARY: Through sequencing analysis, we have demonstrated a distinct landscape of long RNAs (mRNA and lncRNA) in PpIX EVs, with isolation of this EV population resulting in an enrichment of lncRNAs. Considering the emerging diagnostic and prognostic potential of lncRNAs in GBM, exploration of such EVs provides valuable insight into the pathobiology of the tumor of origin. On a broader scale, gene expression analysis of PpIX EV cargo demonstrates at least a ten-fold enrichment of genes that are otherwise buried in the heterogeneous plasma EV background. Furthermore, downstream KEGG orthological analysis of PpIX EV cargo has revealed alignment of 78% of the significant pathways to processes implicated in cancer development and progression. We have identified a panel of genes unique to PpIX EVs, and reflective of the native tumor, that are implicated in GBM pathogenesis including GREM1, MAP4K4, and STAG2. Validation via quantitative and digital PCR of total plasma EVs from patient and healthy cohorts (N = 10, respectively) have yielded similar expression levels, as reflected in sequencing gene expression. Isolation of PpIX EVs, however, insinuates enriched genetic detection. CONCLUSION: In summary, this preliminary cohort of GBM patients has demonstrated the utility of 5-ALA induced PpIX fluorescence outside of its original intentions: facilitating tumor-specific EV identification for the progression of liquid biopsy. These findings are an inviting breakthrough in the development of individualized disease detection and monitoring. Citation Format: Tiffaney Hsia, Anudeep Yekula, Syeda M. Batool, Bob S. Carter, Leonora Balaj. Novel approach for glioblastoma characterization via tumor specific extracellular vesicles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5175.
Abstract 2349: SAP30, a novel drug response specific transcription factor in high-risk neuroblastoma
Authors: Philip Prathipati, Anup S. Pathania, Nagendra K. Chaturvedi, Subash C. Gupta, Siddappa N. Byrareddy, Don W. Coulter, Kishore B. Challagundla
Journal: Cancer Research (2022)

Abstract Neuroblastoma is the most devastating extracranial solid malignancy in children. Despite an intense treatment regimen, the prognosis for high-risk neuroblastoma patients remains poor, with less than 40% survival. So far, MYCN status/amplification is considered the most prognostic factor but corresponds to only 25% of neuroblastoma patients. Therefore, it is essential to identify a better prognosis and prediction marker of therapy response in neuroblastoma patients. The identification of master regulators with good prognostic and drug response abilities are not successful due to the complexity and lack of data-driven bioinformatic workflows. We applied robust bioinformatic data mining tools such as Weighted Gene Co-expression Network Analysis, cisTarget, and Single-Cell rEgulatory Network Inference and Clustering on three neuroblastoma patient datasets (n=1252). We found Sin3A Associated Protein 30 (Sap30), a driver transcription factor positively associated with high-risk, progression, stage 4, and poor survival in high-risk neuroblastoma patient cohorts. Tumors of high-risk neuroblastoma patients and relapse-specific patient-derived xenografts showed higher Sap30 levels. The Genomics of Drug Sensitivity in Cancer, The Cancer Cell Line Encyclopedia, and CRISPR-Cas9 screens indicated that Sap30 essentiality is associated with Cisplatin resistance and further showed higher levels in Cisplatin resistant patient-derived xenograft tumor cell lines. The silencing of Sap30 in cells reduced cell growth, induced cell death, mitochondrial membrane potential loss in vitro, and reduced tumorigenicity in vivo. Altogether, these results indicate that Sap30 is a novel prognostic and Cisplatin resistant marker and thus a potential drug target in high-risk neuroblastoma patients. Citation Format: Philip Prathipati, Anup S. Pathania, Nagendra K. Chaturvedi, Subash C. Gupta, Siddappa N. Byrareddy, Don W. Coulter, Kishore B. Challagundla. SAP30, a novel drug response specific transcription factor in high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2349.
Optogenetics for visual restoration: From proof of principle to translational challenges
Authors: Moritz Lindner, Michael J. Gilhooley, Steven Hughes, Mark W. Hankins
Journal: Progress in Retinal and Eye Research (2022)

Degenerative retinal disorders are a diverse family of diseases commonly leading to irreversible photoreceptor death, while leaving the inner retina relatively intact. Over recent years, innovative gene replacement therapies aiming to halt the progression of certain inherited retinal disorders have made their way into clinics. By rendering surviving retinal neurons light sensitive optogenetic gene therapy now offers a feasible treatment option that can restore lost vision, even in late disease stages and widely independent of the underlying cause of degeneration. Since proof-of-concept almost fifteen years ago, this field has rapidly evolved and a detailed first report on a treated patient has recently been published. In this article, we provide a review of optogenetic approaches for vision restoration. We discuss the currently available optogenetic tools and their relative advantages and disadvantages. Possible cellular targets will be discussed and we will address the question how retinal remodelling may affect the choice of the target and to what extent it may limit the outcomes of optogenetic vision restoration. Finally, we will analyse the evidence for and against optogenetic tool mediated toxicity and will discuss the challenges associated with clinical translation of this promising therapeutic concept.